The paracaspase MALT1 (Mucosa Associated Lymphoma Translocation 1 gene) is frequently activated in lymphoma. It functions as an activator of the NF-?B and JNK signaling pathways through sequence-specific proteolysis of a handful of substrates including CYLD, A20, RelB and Bcl10. Inhibition of MALT1 with the medicinally active phenothiazine compounds has proven to be very effective for the cure of the most aggressive and otherwise untreatable B-cell lymphoma. To date, little is understood about the role of MALT1 in other solid cancers such as melanoma which, despite recent advances in immunotherapy or BRAF600E/MEK oncogene-targeted therapies, continues to be the most deadly form of skin cancer. The goal of this study is to explore the role of MALT1 and its downstream targets in melanoma growth and metastasis. Towards this end, our preliminary studies have demonstrated that CYLD, a potential target of MALT1, is significantly reduced in metastatic melanoma cells, and that forced expression of CYLD inhibits melanoma growth and metastasis through the suppression of the NF-?B and JNK signaling pathways. In contrast, MALT1 is significantly increased in metastatic and vertical growth phase melanoma cells as compared to normal and radial growth phase melanoma cells. ShRNA-mediated gene silencing of MALT1 in a metastatic human melanoma cell line A2058 slows cell growth both in vitro and in vivo, and inhibits metastasis in vivo. Based on these findings, we hypothesize that MALT1 has an important role in melanoma growth and metastasis and is a potential target for combination therapies. This hypothesis will be tested in two separate Aims. Aim I is to determine the role of MALT1 and its downstream targets in melanoma growth, survival and metastasis. Aim II is to determine the effects of genetic MALT1-inhibition on BRAF600E/MEK-targeted therapies. We believe that findings of this study will lead to a better mechanistic understanding of melanoma pathogenesis, and provide insights to therapeutic strategies that may be translated into clinical applications.